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PubMed2026

Both L-Lactyl and D-Lactyl Enantiomers Modify Histones in Mouse Testis.

Dynamic histone posttranslational modifications are crucial to precisely orchestrate gene expression programs. The recently discovered histone lysine lactylation has already been explored in various pathological contexts, but less in normal tissues. This modification exists as two enantiomers, L- and D-lactylation; the former may more likely modify histones due to abundant L-lactate produced by glycolysis. Here, we report the identification by proteomics of L- and D-lactylation on lysines of histones H3 and H4 in mouse testis. We developed a targeted proteomic analysis of histone peptides using synthetic sequences modified by L- or D-lactyl, to acquire reliable identification and quantification data. Some histone peptides bearing either enantiomer are separated by reversed-phase chromatography. Interestingly, despite the fact that L-lactate is much more abundant than D-lactate in mouse testis, we estimated abundance ratios of L-over D-lactylation to lie between 0.4 and 1.6 on seven residues of histones H3 and H4. Next, targeted proteomic analyses were performed on histones extracted from meiotic and postmeiotic male germ cells (spermatocytes and round spermatids, respectively), which are known to use L-lactate as a main source of energy. Nonetheless, residues 18 and 23 of histone H3 (H3K18 and H3K23) were reliably quantified and shown to harbor balanced amounts of both enantiomers. The stoichiometry of lactylation is low over the whole sequence of H3 and H4, representing about 0.01 to 0.44%: this contrasts with acetylation which exists at up to 25 to 35% relative abundances on some N-terminal lysines. Yet, lactylation appears to be more abundant than acetylation on the C-terminal half of H3 and H4, where the latter modification is scarce. Collectively, our results suggest a mechanism producing a mixture of the two enantiomers of lactate, or of a more direct substrate for lactylation, that leads to the modification of histones by L- and D-lactylation.

Animals↗
PubMed2026

Hexaconazole enantiomers drive the dissemination and risks of antibiotic resistance genes in the soil-earthworm system.

Chiral fungicides constitute a substantial proportion of commonly used pesticides; however, the spread of antibiotic resistance genes (ARGs) in agricultural settings under repeated exposure to different enantiomers is still unclear. Here, the prevalence and potential risks of ARGs were investigated in the soil-earthworm ecosystem when exposed to hexaconazole (HEX) enantiomers. Metagenomic analysis indicated that R-HEX and S-HEX facilitated the dissemination of ARGs in soil without earthworms, but this effect diminished with successive exposures. Notably, S-HEX exhibited a greater effect on ARG profiles compared to R-HEX. Furthermore, HEX enantiomers, particularly S-HEX, increased the mobility potential of ARGs and enhanced host pathogenicity, thereby contributing to elevated ecological risks. Specifically, exposure to the HEX enantiomer led to an enrichment of dominant pathogenic ARG hosts, such as Enterobacteriaceae. Importantly, earthworms alleviated the enantiomer-driven dissemination of ARGs and weakened their association with mobile genetic elements (MGEs). Overall, this study offers novel perspectives on the enantiomer-driven propagation of ARGs induced by the chiral pesticide hexaconazole in soil and highlights the role of earthworms in mitigating ARG contamination. These findings contribute significantly to the risk assessment and remediation strategies for chiral pesticides.

Animals↗
PubMed2025

Engineering Polyketide Stereocenters with Ketoreductase Domain Exchanges.

Polyketide synthases (PKSs) are versatile biosynthetic megasynthases capable of producing a diverse range of natural products with many applications, including in pharmaceuticals. The stereochemical precision of PKSs makes them a powerful tool for engineering tailored, unnatural polyketides; however, modifying the stereocenters of a PKS product while maintaining production levels remains a significant challenge. In this study, we systematically tested and evaluated strategies for ketoreductase (KR) domain exchanges, the domain responsible for setting stereocenters of polyketide products. After first optimizing the method for KR exchanges, we then performed 44 KR domain exchanges on three different PKSs to obtain high production of all four stereoisomers in vivo. By testing both one- and two-module PKS systems, we investigated how downstream modules process intermediates with altered stereochemistry and found that the configuration of the α-substituents was critical for gatekeeping by the ketosynthase (KS). To overcome this constraint, we investigated two different strategies for altering the KS domain, including introducing targeted mutations in the downstream KS, and exploring boundaries in exchanging the entire functional unit from the donor PKS. Both strategies successfully modified the KS stereocontrol with distinct trade-offs; the functional unit exchange resulted in higher titer improvements, though it was more likely to break the entire PKS. This study demonstrates a comprehensive approach to successfully engineering all four stereochemical configurations in multiple PKS systems, advancing our understanding of and ability to rationally modify polyketide stereochemistry through multiple engineering strategies.

Polyketides↗
PubMed2026

Total Synthesis and Structural Revision of Rhabdobranin Reveals a Cryptic Gram-Negative Antibiotic.

Gram-negative bacteria present a major clinical challenge but also remain an underexplored source of antibacterial natural products. Resistance-guided genome mining of the entomopathogenic symbiont Xenorhabdus identified the rdb biosynthetic gene cluster, which encodes a putative prodrug antibiotic, pre-rhabdobranin. However, the inability to isolate the proposed active metabolite, rhabdobranin, has prevented direct functional evaluation. Here we report a convergent total synthesis of the proposed structure of pre-rhabdobranin B, which revealed a stereochemical misassignment at the N-terminal arginine residue. Synthesis of both rhabdobranin epimers showed that, although they are nearly indistinguishable by standard analytical methods, inversion at this single stereocenter has a pronounced effect on antibacterial activity. Biological evaluation of the revised rhabdobranin structure revealed potent antibacterial activity against Gram-negative pathogens, including WHO critical-priority carbapenem-resistant Klebsiella pneumoniae. Cellular and biochemical profiling implicated inhibition of protein biosynthesis as its principal antibacterial mechanism. We further show that the GNAT-family acetyltransferase RdbK N-acetylates rhabdobranin, attenuating its activity and establishing a secondary self-resistance mechanism. These findings validate resistance-gene-guided discovery in Gram-negative symbionts as a strategy for uncovering cryptic antibiotics and identify rhabdobranin as a promising scaffold for Gram-negative antibiotic development.

Anti-Bacterial Agents↗
PubMed2026

Cytochrome P450- and Dehydrogenase-Mediated Regiospecific and Stereoselective Formation of β- and γ-Lactones in Drimane-Type Sesquiterpenoid Biosynthesis.

Lactone-containing natural products are important candidates for drug discovery. Drimane-type sesquiterpenes (DTSs), characterized by a bicyclic trans-decalin scaffold, can bear both β- and γ-lactone moieties. While γ-lactone-containing DTSs have frequently been reported, β-lactone-containing derivatives are rare, and their biosynthesis remains unexplored. Here, we identified a biosynthetic gene cluster (dri) in Aspergillus ustus and confirmed ustidrimane A (1), a β- and γ-lactone-containing DTS, as its product. Heterologous gene expression, precursor feeding, and enzymatic investigation provided evidence for the formation of both lactone rings. In both cases, the reaction cascade is initiated by regiospecific (and stereoselective) methyl hydroxylation, followed by regiospecific and stereoselective oxidation of one hydroxymethyl group to an aldehyde. The resulting hemiacetal was proven to be subsequently oxidized to a lactone. The β-lactone formation is catalyzed by two cytochrome P450 enzymes (DriE and DriF), followed by two oxidation steps catalyzed by two dehydrogenases (DriG and DriH). These findings differ entirely from the known β-lactone formation in fatty acid-, PKS-, and NRPS-derived metabolites. The subsequent γ-lactone formation is catalyzed by a P450 (DriJ) and a dehydrogenase (DriD). DriJ has been shown to be involved in both methyl hydroxylation and hemiacetal formation, while DriD is responsible for the hemiacetal oxidation and also contributes moderately to its formation. Collectively, these findings establish a sequential P450/dehydrogenase-mediated oxidative cascade for the construction of two distinct lactone motifs within a single DTS scaffold. Moreover, they provide the first insight into the β-lactone formation in terpenes, thus unveiling a new strategy for the construction of this structural motif.

Lactones↗